Main chemical constituents and mechanism of anti‐tumor action of Solanum nigrum L

Abstract Objective Solanum nigrum L. (SNL) is a natural drugwith diverse bioactive components and multi‐targeted anti‐tumor effects, gaining increasing attention in clinical application. Method and Results This paper reviews the studies on SNL by searching academic databases (Google Scholar, PubMed, Science Direct,and Web of Science, among others), analyzing its chemical compositions (alkaloids, saponins, polysaccharides, and polyphenols, among others), andbriefly describes the anti‐tumor mechanisms of the main components. Discussion This paper discusses the shortcomings of the current research on SNL and proposes corresponding solutions, providing theoretical support for further research on its biological functions and clinical efficacy.


| INTRODUCTION
Cancer is a leading cause of death in humans under 70, with 19 million new incidences and over 9 million cancerrelated deaths in 2020. 1 Although drug therapy is essential in managing cancer, conventional chemotherapy has significant adverse effects that reduce the quality of life of patients. 2Natural medicines are extensively used in clinical applications due to their effectiveness, safety, multicomponent, multi-targeting, and low toxicity and adverse effects. 3,4Therefore, the active ingredients of natural medicines can be extracted and purified to develop anti-tumor drugs.
Solanum nigrum L. (SNL) is a prevalent natural medicine known as Long Kui in China.The extracts of SNL possess tumor-inhibitory effects; Li et al. 5 revealed the inhibitory activity of crude SNL extract against C6 highgrade gliomas in vivo and in vitro.Uen et al. 6 found that SNL aqueous extract could inhibit glucose uptake of human oral cavity cancer cells (SCC-4 cells), consequently, their proliferation by inducing mitochondrial apoptosis pathways.Shokrzadeh et al. 7 found that SNL aqueous extract showed significant cytotoxicity against hepatocellular carcinoma cell lines (HepG2 cells).Lin et al. 8 found that SNL aqueous inhibits HepG2 cell growth by up-regulating autophagy-associated proteins LC3-I/II, activating the caspase pathway-induced apoptosis.Moreover, SNL extract exhibited significant cytotoxicity against human breast cancer cells (MCF-7 cells) 9 by inhibiting their cell viability through mitochondrial function-mediated EMT pathway inhibition. 10Various active components isolated from SNL could inhibit cancer development by inducing cellular autophagy and inhibiting cell invasion. 11,12Therefore, their potential mechanisms of action and related signaling pathways have been extensively studied.Additionally, researchers have focused on combining SNL with other anti-tumor drugs, preparing novel drug delivery formulations.This paper lists the main SNL chemical components and reviews their anti-tumor mechanisms to provide a basis for SNL as a potential anti-tumor drug.

| ALKALOIDS
Alkaloids, as one of the main components isolated from SNL, have received extensive attention in the study of their anti-tumor effects.Haroon Khan et al. summarize the mechanism of action by which alkaloids exert their anticancer potential by inducing cell cycle arrest 53 ; Shailima Rampogu et al. summarized the role of alkaloids isolated from natural plants in breast cancer treatment 54 ; Arijit Mondal et al. provide an overview of alkaloids with anticancer effects and summarize their mechanisms of action 55 ; Caiyan Liu et    NO   NO 18  916.1  NO 16  882.1

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(Continues) the future use of alkaloidal constituents in cancer therapy. 56This part mainly describes the anticancer mechanism of action of alkaloid constituents fractionated from SNL.In this article, we will discuss the effect of various alkaloids derived from SNL on various cancers (Table 5).

| Lung cancer
Lung cancer is highly lethal, with 1.8 million new incidences and 1.6 million mortality cases yearly. 57The SM may exert its anti-lung cancer activity by dose-dependently down-regulates Protein kinase B (AKT/PKB) phosphorylation, SP1, NF-κB subunit p65, and E-prostanoid receptor 4 (EP4) in lung cancer cell lines (A549 and H1299 cells). 58Chen et al. 59 found that SM treatment of A549 and H1299 cells down-regulated EP4, up-regulated ERK1/2 phosphorylation, and decreased DNA methyltransferase 1 (DNMT1) and c-Jun protein expressions.Meanwhile, exogenous EP4 overexpression inhibited ERK1/2 phosphorylation, whereas exogenous DNMT1 overexpression antagonized the inhibitory effect of SM on c-Jun protein expression, and the exogenous c-Jun overexpression blocked the inhibitory effect of SM on lung cancer cells, thus inhibiting ERK1/2 phosphorylation.This suggests that SM down-regulates ERK1/2 phosphorylation by inhibiting EP4 protein expression, decreasing DNMT1 and c-Jun protein expressions to inhibits the growth of lung cancer cells.The SM up-regulates Forkhead box O3 (FOXO3a) protein while down-regulating SP1 protein by decreasing Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation and SP1 protein expression in A549 cells and PC9.Therefore, FOXO3a and SP1, as an upstream signal of Insulin-like growth factor binding protein 1 (IGFBP1), interacted and inhibited IGFBP1 expression in A549 and PC3 cells, exerting the growth inhibitory effect of SM on lung cancer cells. 60hou et al. 61  cells.This was achieved by up-regulating p38-MAPK phosphorylation while down-regulating STAT3 phosphorylation and protein, eventually up-regulating the p21 protein, the downstream effector of STAT3.Tang et al. 62 found that SM treatment of A549 and PC9 cells down-regulated long non-coding RNA HOX transcript antisense RNA (lncRNA HOTAIR) expression and promoter activity while significantly overexpressing miR-214-3p.Moreover, they have revealed that microRNA (miR)-214-3p had a binding site in the 3'-UTR region of lncRNA HOTAIR.Therefore, miR-214-3p binding to HOTAIR suppressed PDPK1, the downstream target      gene of miR-214-3p.This may be the mechanism of action of SM to inhibit NSCLC cell proliferation.SD could inhibit A549 cell invasion by regulating the mitochondrial membrane potential (MMP) pathway and exerting an anti-lung cancer effect. 63The mechanism of action is that SD down-regulates miR-21 while up-regulating Reversion Inducing Cysteine Rich Protein With Kazal Motifs (RECK), a negative MMP regulator, thus inhibiting MMP-2/9 and EMMPRIN mRNA expression.
Zeng et al. 64 found that SN may exert anti-tumor effects by inducing cellular iron death by causing redox imbalance and mitochondrial dysfunction.A dose-dependent increase in Fe 2+ level was observed after SN treatment of Calu-1 and A549 cells, implying that SN may have induced iron death.The mechanism of action is achieved through SN inhibiting the antioxidant enzyme glutathione peroxidase 4 (GPX4), expressing SLC7A11, the cystine/glutamate transporter protein, disrupting cellular redox homeostasis, and inducing mitochondrial ROS amplification and MMP hyperpolarization.

| Liver cancer
Hepatocellular carcinoma is a common and fatal malignancy worldwide, and using natural compounds represents a viable therapeutic option. 65Components including SM, SN, and αtomatine are cytotoxic to hepatocellular carcinoma cells. 66,67Echeverría et al. 68   SM could down-regulate MMP-2/9 expression, blocking the EMT pathway and inhibiting HepG2 cell migration and invasion. 69,70Additionally, SM down-regulates the mRNA and protein levels of the iron death regulator, GSS, and the antioxidant enzyme, GPX4, to disrupt the GPX4induced GSH redox system, promoting the iron death of HepG2/RG cells. 71Ding et al. 72 found that SM could upregulate caspase-3, induce the apoptosis of hepatocellular  carcinoma cell lines (SMMC-7721 and HepG2 cells), and cause cell cycle arrest in the G2/M phase.Moreover, SM can exert anti-tumor effects by regulating non-coding RNAs.Tang et al. 73 found that miR-4726-5p has binding sites with lncRNA HOTTIP and TUG1 and can bind to the 3'-UTR region of the MUC1 protein to regulate its expression.SM treatment in human hepatocellular carcinoma cell lines (HepG2 and Huh-7 cells) reduced MUC1 protein expression and lncRNA HOTTIP and TUG1 while overexpressing miR-4726-5p.This suggests that SM inhibits tumor cell proliferation by regulating the HOTTIP-TUG1/ miR-4726-5p/MUC1 signaling pathway.Additionally, SM induces HepG2 cell autophagy and apoptosis via the LIF/ miR-192-5p/CYR61/AKT axis.Moreover, SM impedes hepatocellular carcinoma invasion by decreasing M2 macrophage polarization and inhibiting the EMT pathway via the LIF/p-STAT3 pathway. 74iu et al. 75 found that SN inhibited the growth of hepatocellular carcinoma cells (HepG2 and QGY-7703 cells) in a time-and dose-dependent manner, with IC50 values of 37.70, 33.88, 35.48 μM and 29.17, 31.83,35.01 μM at 24, 48, and 72 h, respectively.The SN treatment of HepG2 and QGY-7703 cells overexpressed miR-375-3p.miR-375-3p inhibited Colon cancer-associated transcript-1 (CCAT1) expression by binding to the 3'-UTR region of lncRNA CCAT1.Additionally, miR-375-3p and CCAT1 acted as upstream factors to inhibit the protein expression of transcription factor SP1, inhibiting IRF5 transcriptional regulation.SN regulated miR-375-3p and CCAT1 expression through an IFR5 feedback mechanism.Altogether, SN may exert anti-tumor effects through miR-375-3p/ CCAT1/SP1/IRF5 axis.
Nepal et al. 76 loaded αtomatine with mesoporous silica nanoparticles and found that this novel delivery formulation enhanced the antiproliferative activity of αtomatine against hepatocellular carcinoma cells and reduced hemolysis.

| Stomach cancer
Gastric cancer is among the five most common cancers worldwide, accounting for 7.7% of global cancer deaths and ranking fourth, according to global cancer statistics in 2020. 1 Fu et al. 77 found that SM inhibited ERK1/2 phosphorylation and induced lncRNA PINT and NEAT1 expression, inducing apoptosis of gastric cancer cells (SGC7901 and BGC823 cells).Additionally, SM up-regulates caspase-3 and Bax/Bcl-2 ratio while down-regulating mutant p53 protein in human gastric cancer cells (MGC-803) in a dose-dependent manner, inducing apoptosis. 17N inhibits the proliferation of human gastric cancer cell lines (SNU1/5) with IC50 values of 10 and 12.5 μM, respectively.This may be related to the fact that SN upregulates miR-486-5p and targets the 3'-UTR region of PI3KR1.78 Li et al. 79 found that SN dose-dependently inhibited SGC7901 cell proliferation in vitro with an IC50 of 18 μM by down-regulating the apoptotic pathway key protein expression, Bcl-2/xL, inducing apoptosis.
Fujimaki et al. 80 found that tomatidine inhibits gastric cancer cell proliferation by inhibiting type I interferonstimulated genes (ISGs) expression and tumor growth in xenograft tumor model mice.Zhang et al. 81 found αtomatine can inhibit the PI3K/AKT and MAPK signaling pathways inhibit MGC803, BGC823, SGC7901, and SGC7901/DDP cell proliferation, and regulate the transcript levels of key regulators in the EMT pathway to inhibit cell invasion and attenuate the resistance of gastric cancer cells to cisplatin.

| Pancreatic cancer
Pancreatic cancer has the lowest 5-year relative survival rate of 6% and is highly lethal. 82Fan et al. 83 found that the in vivo tumor volume of pancreatic cancer cell (SW1990) hormonal mice was significantly reduced after SD low (10 mg/mL), medium (20 mg/mL), and high (40 mg/mL) dose treatments.Meanwhile, human SW1990 cells showed a dose-dependent up-regulation of Bax, cytochrome C, and cleaved-caspase-9/3 while down-regulation of Bcl-2.COX-2 protein expression and AKT and GSK3β phosphorylation were significantly down-regulated, indicating that SD could significantly inhibit the Cox-2/AKT/GSK3β signaling pathway and induce cell apoptosis.Furthermore, the serum levels of tumor necrosis factor α (TNF-α), interleukin-2 (IL-2), and interferon-γ (IFN-γ) were significantly increased in SW1990-loaded mice, suggesting that SD may exert anti-tumor activity by stimulating the immune function of the body.SM inhibits the AKT/mTOR signaling pathway, induces apoptosis, and inhibits cell migration in pancreatic cancer cells (BxPC-3 cells).Additionally, the inhibitory effect of Fe3O4-SM was more significant than that of SM treatment alone. 84Liang et al. 85 found that SM inhibited the transcriptional regulation of Transcription factor activating enhancer binding protein 2 alpha (TFAP2A) to OTU domain, ubiquitin aldehyde binding 1 (OTUB1) in human pancreatic cancer cells (PANC-1 and CFPAC-1), which in turn inhibited the deubiquitination of SLC7A11 proteins by OTUB1, induced SLC7A11 degradation, activating iron death and inhibiting pancreatic cancer cell progression.

| Colorectal cancer
The cancer statistics in China and the United States in 2022 reported more than 590,000 new colorectal cancer cases and 300,000 deaths. 86Zhuang et al. found 87 that SD inhibited the growth of colon cancer cell lines (HCT-116, HT-29, and SW-480 cells) with IC50 values of 39.43, 44.56, and 50.09μM and dose-dependently blocked colon cancer cells at G2/M phase.SD treatment significantly downregulated p-PI3K, PI3K, p-AKT, AKT, mTOR, p-GSK3β, and βcatenin while up-regulating GSK3β and p-βcatenin, suggesting that SD may inhibit colon cancer cell growth by regulating AKT/GSK3β/β-catenin signaling pathway.Additionally, SD treatment increased E-calmodulin and decreased MMP-2/9/14 at the transcriptional and translational levels, suggesting that SD could inhibit cell invasion and migration via the MMP and EMT pathways.
In vivo experiments showed that the tumor volume and weight of the HCT116 cell transplantation tumor model were significantly reduced, confirming the anti-colorectal cancer effect of SD.
Kim et al. 88 found that αtomatine promoted apoptosisinducing factor (AIF) release from mitochondria into the nucleus and down-regulated survivin expression, inducing apoptosis by a non-caspase-dependent pathway.Ishii et al. 89 found that tomatine inhibited HT-29 cell proliferation by up-regulating the APC gene, the Wnt signaling pathway regulator.Rudolf et al. 90 found that αtomatine was cytotoxic to colorectal cancer cells, which may be related to AIF release from mitochondria and caspaseindependent apoptosis.

| Bladder cancer
Bladder cancer is common worldwide, with ~570,000 new cases and 270,000 deaths recorded in 2020. 1 SN inhibits the growth of human bladder cancer cell lines (T24 and 5637 cells) by binding to the NRP1 protein on the cell membrane.This binding induces extracellular NRP1 protein degradation and impedes NRP1/VEGFA/ VEGFR2 and NRP1/EGFR complex formation on the cell membrane surface, inhibiting ERK, P38, and MEK1/2 phosphorylation. 91

| Prostate cancer
Prostate cancer is the leading cause of cancer deaths in men worldwide. 1Ge et al. 92 found that SM significantly  be related to the reduction of NF-κB activity and downregulation of its downstream gene, Bcl-2 in cells and significant down-regulation of AKT and ERK2/3 phosphorylation.Additionally, αtomatine, in combination with curcumin, significantly inhibits tumor growth in vivo in xenograft tumor mice.Lee et al. 95 found that αtomatine inhibits the PI3K/AKT signaling pathway, up-regulates the pro-apoptotic protein BAD, and down-regulates the anti-apoptotic proteins Bcl-2/xL, as well as having a synergistic effect with paclitaxel to inhibit prostate cancer.

| Nasopharyngeal carcinoma
Nasopharyngeal carcinoma is a malignant epithelial tumor of the apical and lateral walls of the nasopharyngeal cavity with known poor treatment and prognosis. 96CCAT1 is a lncRNA highly expressed in various cancers, 97 and miR7-5p is a tumor-suppressor miRNA. 98,99Wu et al. 100 found that SM reduced the lncRNA CCAT1 expression and enhanced miR7-5p expression in nasopharyngeal carcinoma cell lines (HNE2 and C666-1 cells).Overexpressed miR7-5p enhanced the inhibitory effect of SM on lncRNA CCAT1, and overexpressed lncRNA CCAT1 inhibited the up-regulation of miR7-5p by SM, suggesting that there is an interaction between the two and that it contributes to the inhibition of nasopharyngeal carcinoma cell growth by SM.Additionally, SM dose-dependently inhibited mRNA expression of SP1, which was reversed by lncRNA CCAT1overexpressio.Meanwhile, miR7-5p overexpression enhanced the inhibition of SP1 promoter by SM. overexpression of SP1 did not affect lncRNA CCAT1 expression but reversed the effect of SM on miR7-5p expression and cell growth inhibition in HNE2 and C666-1 cells.The interaction of lncRNA CCAT1 and miR7-5p and SP1 gene expression inhibition may be the mechanism of action of SM in suppressing nasopharyngeal carcinoma.

| Melanoma
Melanoma is a fatal skin cancer with increasing incidence worldwide. 1 Sinani SS et al. 102 found that SM activated the extrinsic mitochondrial death pathway, up-regulated TNFR1, cytochrome c, cathepsin B, and cleaved-caspase-3 protein, inhibiting the growth of melanoma cells (WM115/239 cells).Additionally, tomatine inhibits tumor angiogenesis by up-regulating autophagy markers LC3I/II to induce cellular autophagy in melanoma cell lines (hmel-1 and M3 cells). 103

| Osteosarcoma
Osteosarcoma is the most common primary solid bone malignancy with a high incidence in children and adolescents. 104Treatment of osteosarcoma cells (U2OS1 cells) with SM for 2 h increased mRNA and protein expression levels of p53 and Bax, a key downstream protein for p53 signaling, besides up-regulating caspase-3/9 protein and a substantial loss of MMP.These data suggest that SM activates the mitochondria-mediated apoptotic pathway in U2OS cells. 105

| Multiple myeloma
Multiple myeloma (MM) is a hematological malignancy with more than 32,000 patients newly diagnosed with MM each year. 106It was found that SM inhibited the viability of MM cell lines (ARP-1 and NCI-H929) in a concentration-and time-dependent manner, with IC50 values of 5.36 and 5.23 μM, respectively, the expression levels of Cleaved-Caspase-3 and Bax were up-regulated and Bcl-2 was down-regulated after 24 h of SM (5 μM) treatment, indicating that SM induced apoptosis.Moreover, SM treatment lead to the up-regulation of proteins related to cell death and autophagy in NCI-H929 cells, and the inhibitory effect of SM on MM cells and apoptosis were attenuated by co-treatment with the autophagy inhibitor 3-methyladenine.It was confirmed that activating cellular autophagy to exert anti-MM effects might be an effective way for SM to exert anti-tumor effects. 107

| Hypopharyngeal squamous cell carcinoma
Hypopharyngeal squamous cell carcinoma accounts for 3%-5% of head and neck cancers and is highly aggressive. 108eng et al. 109 found that SM significantly inhibited FaDu cell viability with an IC50 value of 5.17 μM, and in vitro studies found that xenograft tumor mice sustained a significant decrease in tumor volume and weight after continuous daily intravenous injection of SM (5 mg/kg) for 5 weeks.The possible mechanism of action is that SM inhibited the expression of lncRNA HOXA11-As, preventing it from binding miR-155.This prevention up-regulated miR-155 expression, down-regulated the downstream target of miR-155 and c-Myc proteins, and up-regulated the P53 protein.

| Leukemia
Leukemia is a common hematological tumor with increasing morbidity and mortality. 1αtomatine induced apoptosis in human leukemia cancer cell lines (HL-60 cells), which may be closely related to the interaction between αtomatine and cell membrane cholesterol components. 110hao et al. 111 found that αtomatine treatment led to a loss of MMP in the human leukemia cancer cell lines (HL-60 and K562 cells), releasing the AIF from the mitochondria into the nucleus and down-regulating survivin to exert significant cytotoxic effects and inhibit HL-60 xenograft tumor growth.

| Ovarian cancer
Ovarian cancer is a highly lethal female cancer.Wu et al. 112 found that tomatine induced apoptosis in ovarian cancer cell lines (SKOV-3 cells) in a dose-and time-dependent manner and inhibited cell autophagy by down-regulating the Beclin-1 protein.Tomatine treatment down-regulated the PI3K/AKT/mTOR signaling pathway-related proteins, suggesting that tomatine may play an anti-tumor role by inhibiting autophagy and promoting apoptosis.

| Others
Xenograft experiments showed that αsolanine inhibited choriocarcinoma cell growth in nude mice.αsolanine treatment inhibited MMP-2/9 mRNA expression in human choriocarcinoma cells (JEG-3 cells) and reduced MMP-2 activity, suggesting that αsolanine inhibits tumor cell metastasis.αsolanine was not detected as the active form of MMP-2/9 in the cell culture medium, and its role in activating MMPs needs to be further investigated. 113SM up-regulated Bax, caspase 3, cleaved-caspase 3, caspase 7, and cleaved-PARP proteins while down-regulating Bcl-2, XIAP, and PARP proteins in human cholangiocarcinoma cells (QBC939 cells).Therefore, SM may inhibit QBC939 cell survival by affecting apoptosis-related proteins. 114urthermore, SM inhibited the proliferation of cervical cancer cells (HeLa and SiHa cells) by modulating the ERK signaling pathway. 115SM significantly reduced the number of HER2/neu receptors on the cell membrane of the breast cancer cell line (ZR-75-1 cells) and enhanced the sensitivity of breast cancer cells to chemotherapeutic drugs. 116SN regulates NF-κB and MAPK signaling pathways to inhibit p65 phosphorylation to inhibit glioma cell growth. 117Lenka et al. 118 found that αtomatine was cytotoxic to human MCF-7 cells, with no detectable changes in the apoptosis-related protein expressions.Meanwhile, the binding of tomatine to cholesterol reduced the cytotoxicity.Silva et al. 119 found that tomatine and tomatidine treatment activated the PERK/eIF2α pathway and inhibited proteasome 20S activity.Therefore the interference with tumor cell protein homeostasis may be responsible for exerting cytotoxicity against the neuroblastoma cell line (SH-SY5Y).In summary, SNL has multi-component, multipathway and multi-target anticancer characteristics, of which the main active ingredient, solamargine, has the following anticancer mechanisms: induction of cell autophagy and inhibition of cell migration, regulation of Caspase pathway or lncRNA HOXA11-As/miR-155/P53 pathway induces apoptosis, regulation of PI3K/AKT pathway or lncRNA CCAT1/miR7-5p/SP axis inhibits tumor cell growth.Reduces the number of HER2/neu receptors on the cell membrane and enhances sensitivity to the chemotherapeutic drugs.The main anticancer mechanisms of Solasodine include: modulation of the caspase pathway to induce apoptosis, down-regulation of miR-21 and MMPs to inhibit tumor cell migration, modulation of the AKT/GSK-3b/b-catenin signaling pathway and improvement of nuclear translocation of βcatenin to induce apoptosis, modulation of the AKT/ GSK-3b/b-catenin signaling pathway and improvement.The main anti-cancer mechanisms of Solasodine include.Induction of cellular iron death by disrupting cellular redox homeostasis by inhibiting the expression of GPX 4 and SLC7A11, Inhibition of cell proliferation through miR-375-3p/CCAT1/ SP1/IRF5 axis, induction of apoptosis through mitochondrial apoptosis pathway, enhanced ubiquitinated degradation of SLC1A1 to activated iron death, inhibition of MAPK, PI3K/ AKT, NF-κB signaling pathways to induce apoptosis and inhibition of cell proliferation.Tomatine: activates caspase apoptosis signaling pathway, regulates PI3K/ AKT pathway, regulates NF-κB pathway, regulates PERK/eIF2α pathway; α-Solanine inhibits tumor cell invasion, α-Tomatine blocks cell cycle progression inhibition, regulates NF-κB signaling pathway to induce apoptosis.However, most of the above conclusions come from in vitro experimental results and lack validation from in vivo animal models as well as clinical data.Whether alkaloidal active ingredients can provide evidence for SNL as a natural anticancer drug requires further research.

| SAPONINS
Saponins are the most important class of steroids in SNL, and the anticancer potential of saponins has been summarized in the past.Olusola Olalekan Elekofehinti et al. summarized the classification of saponins and the mechanism of anticancer action for the 120 124 This part mainly complements the mechanism of action of the saponin-like components with anticancer activity isolated from SNL (Table 6).

| Lung cancer
Formosanin C is a biologically active steroidal saponin analog isolated from SNL. Treatment of human largecell lung cancer cells (NCI-H460) with different concentrations of Formosanin C for 24 h up-regulated the autophagy marker LC3-II and key protein Beclin-1 in a dose-dependent manner.Formosanin C up-regulated p-JNK while down-regulating p-PI3K, p-AKT, and p-mTOR.Meanwhile, the co-treatment with autophagy inhibitor chloroquine (CQ) induced JNK, PI3K, AKT, and mTOR phosphorylation to normal, suggesting that inhibiting NCI-H460 cell proliferation by formosanin C through autophagy activation may be related to JNK activity activation and PI3K/AKT/mTOR pathway inhibition. 125amilselvam et al. 126 found that βsitosterol treatment of A549 cells for 72 h significantly inhibited cell growth with an IC50 value of 24.7 μM and had no effect on normal human lung cells.This may be because βsitosterol interacts with Cys32 and Leu409 residues on Thioredoxin (Trx1) and Thioredoxin reductase (TrxR1) through hydrogen bonding, respectively.This interaction affects cellular redox homeostasis, promotes ROS accumulation, induces cellular DNA damage, and up-regulates p53/p21 protein, triggering and activating cellular DNA damage.The p53/p21 protein up-regulation activated and triggered mitochondria-mediated apoptosis in A549 and NCI-H460 cells.
Non-small cell lung cancer is a common type of lung cancer, and daucosterol (DS) is a steroidal saponin compound widely found in the plant Lobelia.DS exhibited growth inhibitory effects on A549 cells with an IC50 value of 20.9 μM.The possible mechanism of action is that DS interacted with TrxR, disrupting cellular redox homeostasis.This disruption triggered oxidative stress-mediated apoptosis, including the caspase-apoptosis signaling pathway activation and up-regulating p53 phosphorylation. 127

| Liver cancer
DS treatment of HepG2 and SMMC-7721 cells downregulated βcatenin and p-βcatenin.Co-treatment of DS with SB-216763, a Wnt signaling pathway inhibitor, attenuated the effects of DS on hepatocellular carcinoma cells.These results suggest DS may inhibit HCC cell migration and invasion through the Wnt/β-catenin signaling pathway. 128uong et al. found that βsitosterol dose-dependently inhibited HepG2 and Huh7 cell proliferation, with IC50 values of 0.017 and 0.021 μM, respectively, which may be related to activating caspase-3/9 and inducing apoptosis by βsitosterol. 129ATH et al. found that uttroside B exhibited significant cytotoxicity against HepG2 cells, with an IC50 value of 500 μM, significantly reducing the tumor volume in xenograft tumor model mice.In vitro experiments revealed that treatment with uttroside B (500 μM) down-regulated JNK, p38, and p42/44 (ERK1/2) phosphorylation and inhibited Phorbol 12-myristate 13-acetate (PMA)-induced phosphorylation.Moreover, mTOR phosphorylation was reduced in a time-dependent manner in HepG2 cells.These suggest that uttroside B may exert anti-tumor effects by modulating the MAPK and mTOR signaling pathways, besides a dose-dependent up-regulating cleaved-caspase 7/8/9. 130

| Kidney cancer
Degalactotigonin (DGT) is an SNL-isolated steroidal glycoside with significant cytotoxicity. 131  in the renal cell carcinoma cell cytoplasm by activating LATS1/2 protein phosphorylation and blocks YAP-TEAD1 interaction to down-regulate YAP and its target genes (associated with the Hippo pathway).The expression of YAP and its target genes AMOTL1, AMOTL2, AXL, CTGF, and CYR61 was reduced in DGT-treated 786-O and A498 cells compared to untreated control cells, therefore inhibiting cancer cell proliferation and inducing apoptosis. 132

| Pancreatic cancer
Epidermal Growth Factor Receptor (EGFR) and its family members have a regulatory role in tumor proliferation. 133reatment of PANC-1 cells with different concentrations (0, 1, 3, 10, and 30 μM) of DGT significantly reduced EGFinduced phosphorylation levels of EGFR and inhibited in a concentration-dependent manner the downstream signaling molecules AKT (Ser 473) and ERK (Thr 202/ Tyr 204) phosphorylation.Additionally, 0.3 μM of DGT significantly induced cell cycle arrest in the G0/1 phase, inhibiting the growth effect on the proportion of S-phase cells after EGF treatment.This suggests that DGT induces apoptosis and cell cycle arrest in pancreatic cancer cells by inhibiting the EGFR signaling pathway. 134reatment of human pancreatic cancer cells (MIA-PaCa-2) and human in situ pancreatic adenocarcinoma cells (BXPC-3 cells) with different βsitosterol concentrations (0, 125, 250, and 500 μM) inhibited cancer cell migration and invasion by regulating EMT pathway key molecules (dosedependently down-regulating Snail and vimentin proteins and up-regulating E-cadherin protein), thereby exerting anti-pancreatic cancer activity by inactivating the AKT/ GSK-3 signaling pathway and regulating apoptosis. 135

| Prostate cancer
Gao et al. 136 found that DS treatment of human prostate cancer cells (PC3 and LNCap cells) for 48 h increased c-Jun N-terminal kinase (JNK) phosphorylation and induced cellular autophagy.Meanwhile, the autophagy inhibitor 3-MA and the JNK-specific inhibitor SP600125 could inhibit DS-induced cellular autophagy, suggesting that DS partly inhibits prostate cancer growth by activating the JNK signaling pathway and inducing autophagy.

| Osteosarcoma
Zhao et al. 137 found that DGT inhibited the proliferation of human osteosarcoma cell lines (U2OS, HOS, and MG-63 cells) in vitro, with IC50 values of 12.91-31.46μM.
DGT treatment down-regulated GLI Family Zinc Finger 1 (Gli1) in a dose-dependent manner while up-regulating GSK3β phosphorylation to inhibit GSK3β activity, thus inhibiting cell viability and invasion.Cell viability and invasion were partially restored when transfected into GSK3β knockdown ZOS cells using the overexpression of the Gli1 plasmid.This suggests that DGT may inhibit osteosarcoma cell activity by suppressing GSK3β/Gli1 activation.
In summary, among several major saponin active ingredients of SNL, Formosanin C inhibited the PI3K/AKT/ mTOR pathway to induce cellular autophagy; βsitosterol induced mitochondria-mediated apoptosis, activated the caspase pathway to activate apoptosis, and regulated the AKT/GSK-3 signaling pathway to inhibit cell migration.Binding of Daucosterol to TrxR interferes with cellular redox homeostasis to activate the caspase-3 apoptosis signaling pathway, and inhibits migration and invasion of HCC cells through the Wnt/β-linker protein signaling pathway.Activation of the jnk signaling pathway induces cellular autophagy; uttroside B activation of caspase pathway to induce apoptosis.Degalactotigonin inhibits the EGFR signaling pathway to induce apoptosis and cell cycle arrest, and the Hedgehog/Gli1 Pathway to inhibit tumor cell migration and invasion.In order to be able to make a case for SNL as a natural anticancer drug, the long-term effects, bioavailability and anticancer activity of these components in different tumor cells need to be investigated, and also supplemented with in vivo animal models to confirm their efficacy and safety.

| POLYSACCHARIDES
Polysaccharide components have been less studied due to reasons such as difficulty in extraction, complexity of composition, and most of the active components have not been identified, etc.This part of the study focuses on the anti-tumor mechanism of action of polysaccharides isolated from Lobelia (Table 7).

| Lung cancer
Pu et al. 138 isolated a homogeneous polysaccharide from SNL (SNLP-1) and analyzed its effects on macrophages and Lewis lung carcinoma (LLC) tumor model mice.The results showed that SNLP-1 significantly up-regulated mRNAs and proteins of key nodes in the TLR4 signaling pathway, including TLR4, MyD88, TRAF6, p-NF-κB, p-c-Jun, and induced NO, TNF-α, and IL-6 release from macrophages.In vivo results showed that after 20 days of gavage administration of SNLP-1 (4 mg/kg/day), macrophages in the LLC tumor model mice significantly down-regulated NO, TNF-α, and IL-6, reducing tumor volume and weight.Additionally, SNLP-1 significantly up-regulated cytokine levels, including IL-2, IFN-γ, and TNF.Altogether, SNLP-1 can enhance immune activity and play an anti-tumor role by regulating the TLR4mediated MyD88-dependent signaling pathway.

| Breast cancer
Breast cancer is the most common female cancer in clinical practice, 139 and SN-ppF3, a polysaccharide component extracted from SNL, inhibits mouse breast cancer.The in vivo experiments showed that oral administration of 250 and 500 mg/kg of SN-ppF3 for 10 days inhibited tumor growth in 54% and 65% of mice, respectively.The analysis of cytokine levels showed that TNF-α was elevated by ~14% compared with the control group and up-regulated other cytokines, IFN-γ (~22%) and IL-4 (~12%).Immunofluorescence assay showed that the fluorescence intensity of natural killer cells, CD8 + T cells, and macrophages was significantly enhanced after SN-ppF3 treatment, suggesting that SN-ppF3 exerts its anti-tumor effects by enhancing the immune response. 140

| Cervical cancer
Cervical cancer is a highly prevalent and lethal disease in women worldwide, with ~600,000 cases and 300,000 deaths worldwide in 2020. 1 SNLP induces apoptosis in cervical cancer lines (U14 cells).In vivo studies showed that 180 and 360 mg/kg SNLP administered by gavage for 12 consecutive days significantly reduced tumor weight and volume in xenograft tumor-bearing mice.Moreover, SNLP significantly down-regulated Bcl-2 and mutant p53 proteins while up-regulating Bax, suggesting that SNLP exerts anti-tumor effects by inducing apoptosis through apoptotic signaling regulation. 141i et al. 29 isolated three homogeneous polysaccharides, SNLP-1a/b/c, from SNL, all of which reduced tumor weights in a mouse cervical cancer model.The inhibitory effect on tumor growth after treatment with SNLP-1a was the most significant.Immunohistochemical staining of thymus tissue sections showed that SNLP-1a could restore their normal Bcl-2/Bax ratio and reduce the damage caused by tumor invasion.Additionally, the ratio of CD4 + /8 + T-lymphocyte subpopulation was increased from 0.77 to 1.97 and 2.62, respectively.SNLP-1a exerts anti-tumor activity by inhibiting tumor-induced apoptosis of thymus lymphocytes in vivo and enhancing the immune response.
In summary, among the several polysaccharide components isolated from SNL, SNLP-1 promotes immune activity through the activation of MyD88-dependent signaling pathway by TLR4, and the rest of the polysaccharide components also exert anti-tumor activity mainly through the pathways of enhancing immunity and inducing apoptosis, etc. Due to factors such as the instability and difficulty of isolation of the polysaccharide components, which have hindered the study of this kind of components, more research is needed to confirm the anti-tumor activity of the polysaccharide components in SNL.

| POLYPHENOLS
Several studies have been conducted to show the inhibitory effects of phenolic acid components contained in SNL, including GA, ferulic acid, caffeic acid, and quercetin, on breast, lung, liver, and prostate cancers.Gupta Ashutosh et al. 142 and Marjorie Reyes-Farias et al. 143 described the anti-tumor mechanism of ferulic acid and quercetin, respectively.Ashrafizadeh Milad et al. 144 and Alam Manzar et al. 145 summarized the mechanism of action of GA and caffeic acid in cancer therapy, respectively.Jiang et al. 146 outlined the potential role of GA as an anti-tumor drug.Kuar et al. 147 analyzed the characteristics and anti-tumor effects of ferulic acid as a multi-target therapeutic agent.
Shukla et al. 148 described the novel delivery system of ferulic acid for its anti-tumor effects.Bastidas et al. 149 summarized the important studies of caffeic acid and its derivatives in cancer therapy.This section will add to the recent studies on polyphenolic components extracted from SNL (Table 8).

| Breast cancer
The aqueous extract of SN leaves has significant cytotoxic effects on human breast cancer cells (AU565).
After treatment with different doses (0.028 and 0.113 μg/ mL) of aqueous extract of SN leaves, the expression of autophagy marker LC-3 protein was increased by the low-dose treatment, reaching the peak value at 6-12 h.Meanwhile, after 48 h of the high-dose treatment, LC-3 protein and apoptosis marker c-PARP were up-regulated.This indicates that SN leaf aqueous extract exerts antitumor effects by mediating different mechanisms in a dose-dependent manner. 31 et al. 155 found that quercetin induced transcription factor EB (TFEB) nuclear translocation, activated lysosomal activity, promoted ferritin degradation, and increased intracellular ferric ions, inducing iron death in breast cancer cells.Safa et al. 156 found that GA had significant cytotoxicity against MDA-MB-231 breast cancer cells, with an IC50 of 0.2578 μM.GA increased cell membrane permeability, cytochrome c levels, and caspase-8/9 activities while significantly decreasing mitochondrial membrane permeability and inducing apoptosis.This suggests that GA may be a potential therapeutic agent for triplenegative breast cancer.

| Stomach cancer
Liao et al. 157 induced GES-1 cells with N-methyl-N′nitro-N-nitrosoguanidine (MNNG) to establish gastric precancerous lesions (GPL) model cells, revealing that GA down-regulated EMT pathway-related proteins, Ncadherin and vimentin while up-regulating E-cadherin.Additionally, GA down-regulated the key proteins of the Wnt/β-catenin signaling pathway, Wnt 10B and βcatenin, and its downstream protein Cyclin D1.Meanwhile, the Wnt activator, Wnt agonist 1, could reverse this regulatory effect of GA on GPL model cells.This suggests that GA attenuates GPL by inhibiting the Wnt/β-catenin and EMT signaling pathways.

| Colorectal cancer
In their study, Bhatiya et al 158 observed that Quercetin effectively suppressed the proliferation of colon cancer cells by modulating the expression of the anti-aging genes SIRT-6 and Klotho.Additionally, Lee et al 159 demonstrated that Quercetin inhibited the Resistin-induced TLR4-mediated NLRP3 expression and ERK phosphorylation levels in HCT-116 cells, thereby enhancing the susceptibility of human colon cancer cells to 5-Fluorouracil.Quercetin was observed to exhibit a substantial inhibition of cell invasion, while also activating the JNK signaling pathway.Additionally, the antiproliferative impact on colonic cancer cells induced by SP600125, a JNK pathway inhibitor, was effectively reversed by quercetin.These findings strongly imply that quercetin exerts its inhibitory effects on the migration and invasion of colon cancer cells through the modulation of the JNK signaling pathway. 160iu et al 161 developed a conatumumab decorated, reactive oxygen species sensitive irinotecan prodrug and quercetin co-loaded nanostructured lipid carriers, which significantly inhibited the growth of HT-29 cells and enhanced drug targeting without systemic without systematicity.

| Prostate cancer
The study revealed that radiotherapy had the effect of increasing the expression of ARv7 in CWR22Rv1 and VCaP cells.This increase in ARv7 expression was found to potentially decrease the sensitivity of these cells to radiation by upregulating the expression of circRNA NHS.It was further observed that circRNA NHS binds to miR-512-5p, leading to an increase in the protein expression of XRCC5.Additionally, the administration of Quercetin was found to significantly reduce the expression of ARv7 at both the mRNA and protein levels in CWR22Rv1 and VCaP cells.Furthermore, Quercetin was observed to down-regulate the ARv7-mediated circNHS/miR-512-5p/XRCC5 signaling pathway, thereby enhancing the radiosensitivity of prostate cancer.This finding was reported in a study by. 162

| Squamous cell carcinoma of the tongue
Huang et al 163 discovered that quercetin facilitated JNK activation in order to regulate the ERK1/2 and GSK3-α/βmediated mitochondria-dependent apoptotic signaling pathway, thereby inducing apoptosis in squamous cell carcinoma of the tongue.This conclusion was primarily derived from the observation that quercetin notably elevated the protein expression levels of p-ERK, p-JNK1/2, and p-GSK3-α/β in SAS cells and exerted its apoptotic effects by modulating the expression of proteins associated with the mitochondrial apoptotic signaling pathway.
In summary, Quercetin can regulate circNHS/ miR-512-5p/XRCC5 signaling pathway, mitochondriadependent apoptosis signaling pathway, JNK signaling pathway, Regulation of the expression of anti-aging genes SIRT-6 and Klotho, induction of cellular iron death, induction of autophagy and apoptosis, and enhancement of drug sensitivity and targeting; gallic acid modulates the PI3K/Akt pathway, the Hippo-YAP signaling pathway, activates the caspase pathway, and inhibits the Wnt/βlinker protein signaling pathway and the EMT pathway.In order to better establish SNL as a safe and effective natural anticancer drug, more mechanistic studies, in vivo animal model experiments and human clinical studies are needed.

| SUMMARY AND DISCUSSION
This paper summarizes the results of recent studies on the chemical composition of SNL and describes the antitumor mechanism of its active components.A variety of active components such as sterols and saponins, alkaloids, polysaccharides, and phenolic acids extracted from SNL possess anti-tumor activity.These active components exert their anti-tumor activities by regulating various signaling pathways to induce apoptosis, cell autophagy, iron death of tumor cells, inhibition of tumor cell invasion and migration, and other events.Most of the active ingredients induced apoptosis mainly by regulating the caspase pathway and mitochondrial apoptosis pathway, and some of the active ingredients could affect the cellular redox homeostasis to activate the caspase-3 apoptosis signaling pathway.In addition, by enhancing the ubiquitination degradation of SLC1A1 or disrupting cellular redox homeostasis, they can activate iron death in tumor cells.The active ingredients can regulate the Wnt/β-cyclin signaling pathway and EMT pathway to inhibit the migration or invasion of tumor cells.Some active ingredients inhibit tumor cell growth by enhancing immune response, improving drug sensitivity and targeting.In addition, some active ingredients inhibit tumor cell growth by regulating certain lncRNA or miRNA-related pathways involved.
Current research on SNL has focused on cellular and animal models, and the actual effects on the human body have not yet been fully demonstrated and need to be further investigated in conjunction with the available clinical evidence.In addition, most studies have investigated the anti-tumor effects of individual components, and the synergistic effects of different components on anti-tumor need to be investigated.The active components of SNL can improve the efficacy of clinical chemotherapeutic drugs and weaken the drug resistance of cancer cells.Therefore, the establishment of a new delivery vehicle to improve drug bio-availability and drug targeting to tumor tissues is an important direction for the development of potential anti-tumor drugs.In addition, SNL contains potentially toxic compounds, and better quality control standards need to be established to ensure the safety of SNL.
In summary, SNL, as a widely distributed natural drug, has potential therapeutic effects on a wide range of tumors, and the active components of SNL inhibit tumor development through a multi-pathway and multi-target mechanism of action.This paper describes the active components and mechanism of action of SNL, revealing the great potential and broad research prospects of SNL as a potential anti-tumor drug (Figure 5).

F I G U R E 2
Structural formula for saponin-like and triterpenoid compounds.

F I G U R E 3
Structural formula for polyphenolic and other compounds.

F I G U R E 4 5 SMMC
inhibited the proliferation of human prostate cancer cells (PC3 and DU145 cells), with IC50 values of 3.25 and 4.52 μM, respectively.The levels of AKT phosphorylation were dose-dependently reduced in PC3 and DU145 cells after 24 h of SM treatment, consistent with the results of the IHC staining analysis of the xenograft model mice after 8 weeks of administration.This suggests that SM inhibits the PI3K/AKT pathway to inhibit prostate cancer cell proliferation.Moreover, SM combined with docetaxel enhanced the antiproliferative effect on prostate cancer.Lee et al.93 identified the potential pathway for αtomatine to inhibit prostate cancer to be through inhibiting NF-κB activity and NF-κBdependent expression of anti-apoptotic proteins (c-IAP1, c-IAP2, Bcl-2/xL, XIAP, and survivin).The mechanism of action is that αtomatine inhibits TNF-αinduced activation of AKT and Inhibitor of kappa B Kinase (IKK).Additionally, it hinders inhibitor kappa B alpha (IκBα) phosphorylation, reducing the nuclear translocations of NF-κB p50 and p65.This inhibition of NF-κB activity ultimately induces cell apoptosis.Huang et al.94 found that the combination of αtomatine and curcumin inhibited prostate cancer cell growth, which may Structural formula for substituent group.Anti-tumor mechanism of alkaloid components./AKT and down-regulation of SP1 and p65 expression inhibited EP4 expression A549 cells, H1299 cells Inhibition of EP4 protein expression down-regulated ERK1/2 phosphorylation, which in turn led to decreased protein expression levels of DNMT1 and c-Jun A549 cells, PC9 cells Inhibition of STAT3 phosphorylation, up-regulation of FOXO3a protein levels, reduction of SP1 protein expression and inhibition of IGFBP1 expression levels SMH1650 cells, A549 cells Promotes phosphorylation of p38-MAPK, inhibits phosphorylation and protein expression of Stat3, and upregulates protein expression of Stat3 downstream effector p21 A549 cells, PC9 cells Increased expression of miR-214-3p and inhibition of miR-214-3p downstream target gene PDPK1 by binding to HOTAIR Solasodine A549 cells Inhibition of miR-21 expression leads to increased RECK expression, which inhibits mRNA expression of MMP-2, -9, and EMMPRIN Solasonine Calu-1 cells, A549 cells Inhibited expression of GPX4, SLC7A11, disrupted cellular redox homeostasis, induced amplification of mitochondrial ROS and hyperpolarization of mitochondrial membrane potential (MMP), induced cellular of Bcl-2 and Bcl-XL expression and concomitant up-regulation of Bax and Bad expression activates the caspase apoptosis signaling pathway Solamargine HepG2 cells Down-regulation of MMP-2 and MMP-9 expression and activity HepG2 cells Blocking the EMT process HepG2 cells, HepRG cells Inhibition of GSS and GPX4 expression induces disruption of the GSH redox system and activates iron death of the lncRNAs HOTTIP and TUG1 upregulated miR-4726-5p, which in turn inhibited the MUC1 protein HepG2 cells LIF/miR-192-5p/CYR61/AKT axis induces autophagy in HepG2 cells Solasonine HepG2 cells, QGY-7703 cells Inhibition of cell proliferation through miR-375-3p, CCAT1, SP1 and of caspase-3 expression; up-regulation of Bax/Bcl-2 ratio and down-regulation of mutant p53 protein expression Solasonine SNU1 cells, SNU5 cells Upregulation of miR-486-5p expression specifically targets phosphatidylinositol 3-kinase regulatory subunit 1 the expression of COX-2, decreases the phosphorylation of p-AKT and p-GSK3β, enhances the expression of caspase-3 and 9, increases the expression of Bax protein, and decreases the expression of Bcl-2 protein.inhibited its protein expression and blocking TFAP2A binding to the OTUB1 promoter region enhanced ubiquitinated degradation of SLC1A1 and activated iron death Colorectal cancer Solasodine HCT 116 cells, HT-29 cells和SW480 cells, BALB/c/nu/ nu nude mice Modulation of the AKT/GSK-3b/b-catenin signaling pathway and improvement of nuclear translocation of βcatenin to regulate downstream genes, with a decrease in the protein levels of Bcl-2, Bcl-xl and Caspase-9 and an increase in the protein levels of Bax, Cleaved-Caspase-8, Cleaved-Caspase-3 and Cleaved-PARP 1 in a dose-dependent manner α-Tomatine CT-26 cell Regulation of non-Caspase-dependent pathways HT-29 cells Inhibition of APC gene expression HCT-116 cells, LoVo cells, SW480 cells, SW620 cells, SW48 cells Induction of mitochondrial release of AIF and caspaseindependent apoptosis Bladder cancer Solasonine T24 cells, 5637 cells Binds to NRP 1 and induces NRP 1 protein degradation, inhibits NRP1/VEGFA/VEGFR2 and NRP1/EGFR complex formation, and inhibits MAPK and PI3K/AKT signaling pathways Prostate cancer Solamargine PC3 cells, DU145 cells Inhibition of PI3K/AKT pathway enhances docetaxel sensitivity in cancer cells α-Tomatine PC-3 cells Inhibition of TNF-αinduced Akt and IKK activation and phosphorylation of IκBα reduced NF-κB p50 and p65 nuclear translocation and inhibited NF-κB activity PC-3 cells Reduction of NF-κB activity and inhibition of its downstream gene Bcl-2 expression in cells PC-3 cells Inhibition of the PI3K/Akt signaling pathway upregulates the expression of the pro-apoptotic protein BAD and downregulates the expression of the anti-apoptotic proteins Bcl-2 and Bcl-HOXA11-As expression prevented lncRNA HOXA11-AS from binding miR-155, which resulted in up-regulation of miR-155 expression level, inhibited the expression of c-Myc, a target gene downstream of miR-155, and down-regulated c-Myc protein and up-regulated P53 protein expression level WANG et al. found that DGT inhibited the proliferation of renal cell carcinoma cell lines (786-O and A498 cells) with IC50 values of 7.52-10.21μM.The anti-tumor mechanism of DGT is related to the key effector protein, yes-associated protein (YAP), in the Hippo pathway.DGT induces YAP retention T A B L E 6 Anti-tumor mechanism of saponins. of DS to TrxR interfered with cellular redox homeostasis, activated the caspase-3 apoptosis signaling pathway, and up-regulated the level of phosphorylation of the tumor suppressor protein of MAPK and mTOR signaling pathways, activation of caspase pathway to induce apoptosis 130 Kidney cancer Degalactotigonin 786-O cells, A498 cells Phosphorylation-activated LATS1/2 induces YAP retention in the cytoplasm of RCC cells and blocks the interaction between YAP and TEAD1 to inhibit YAP mRNA expression and reduce YAP target gene expression 132 Pancreatic cancer Degalactotigonin PANC1 cells reduced the level of EGF-induced EGFR phosphorylation and inhibited phosphorylation of the downstream signaling molecules AKT (Ser 473) and ERK (Thr 202/Tyr 204).

F I G U R E 5
Main chemical constituents of SNL.
Anti-tumor mechanism of polysaccharides.